: The proposed studies focus on the mechanisms and consequences of the interaction of ER with 3 nuclear receptor interacting proteins, the corepressors BRCA1 and N-CoR and the coactivator CBP. Aim 1 is to map the binding regions in the ER LBD for these factors using a battery of ER LBD mutants. Aim 2 will determine the regions of these coactivators and corepressors that interact with the ER LBD. Synthetic peptides or recombinant proteins will be used in co-crystal structure determinations to investigate the structure of the ER LBD and ER DBD-LBD complexes. Aim 3 will establish the physiological role of the interaction of BRCA1 with the ER LBD in mammary gland and prostate. Homologous recombination will be used to create mice bearing mutations in the ER LBD that specifically block interactions with BRCA1. The primary tissues to be examined include the mammary gland, ovary, and prostate.